Cancer Research UK Beatson Institute, Glasgow G611BD, UK.
Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven B-3000, Belgium.
Nat Commun. 2017 Feb 15;8:14206. doi: 10.1038/ncomms14206.
The secretome of cancer and stromal cells generates a microenvironment that contributes to tumour cell invasion and angiogenesis. Here we compare the secretome of human mammary normal and cancer-associated fibroblasts (CAFs). We discover that the chloride intracellular channel protein 3 (CLIC3) is an abundant component of the CAF secretome. Secreted CLIC3 promotes invasive behaviour of endothelial cells to drive angiogenesis and increases invasiveness of cancer cells both in vivo and in 3D cell culture models, and this requires active transglutaminase-2 (TGM2). CLIC3 acts as a glutathione-dependent oxidoreductase that reduces TGM2 and regulates TGM2 binding to its cofactors. Finally, CLIC3 is also secreted by cancer cells, is abundant in the stromal and tumour compartments of aggressive ovarian cancers and its levels correlate with poor clinical outcome. This work reveals a previously undescribed invasive mechanism whereby the secretion of a glutathione-dependent oxidoreductase drives angiogenesis and cancer progression by promoting TGM2-dependent invasion.
肿瘤细胞和基质细胞的分泌组会生成一种微环境，有助于肿瘤细胞的侵袭和血管生成。在这里，我们比较了人乳腺正常成纤维细胞和癌相关成纤维细胞（CAFs）的分泌组。我们发现氯离子细胞内通道蛋白 3（CLIC3）是 CAF 分泌组的丰富成分。分泌的 CLIC3 促进内皮细胞的侵袭行为，从而促进血管生成，并增加体内和 3D 细胞培养模型中癌细胞的侵袭性，这需要活性转谷氨酰胺酶-2（TGM2）。CLIC3 作为谷胱甘肽依赖性氧化还原酶起作用，可还原 TGM2 并调节 TGM2 与其辅因子的结合。最后，CLIC3 也被癌细胞分泌，在侵袭性卵巢癌的基质和肿瘤区室中含量丰富，其水平与不良临床结局相关。这项工作揭示了一种以前未被描述的侵袭机制，即谷胱甘肽依赖性氧化还原酶的分泌通过促进 TGM2 依赖性侵袭来驱动血管生成和癌症进展。
